A major problem encountered with topical delivery of ophthalmic drugs is the rapid and extensive precorneal loss caused by drainage and high tear fluid turnover. After instillation of an eye-drop, typically less than 5% of the applied drug penetrates the cornea and reaches intraocular tissues. After topical administration of an ophthalmic drug solution, the drug is first diluted by the lacrimal fluid. The contact time of drug with ocular tissue is relatively short (1–2 min) because of the permanent production of lacrymal fluid (0.5–2.2 μL/min). Then, approximately half of the drug flows through the upper canaliculus and the other half, through the lower canaliculus into the lacrimal sac, which opens into the nasolacrimal duct. Drainage of lacrymal fluid during blinking (every 12 s) towards the nasolacrimal duct induces a rapid elimination of the dose.
Several different approaches have been attempted in order to overcome the disadvantages of solution-based eye-drops, outlined above. Specifically, various ophthalmic delivery systems, such as hydrogels, micro-and nanoparticles, liposomes, and inserts have all been investigated. Most of the formulation efforts have been aimed at maximizing ocular drug absorption through prolongation of the drug residence time in the cornea and conjunctival sac. Control of residence time has been accomplished to a minimal extent through the use of viscosifying agents added to aqueous solution, and to a greater extent, through the use of diffusion-controlled, non-erodible polymeric inserts (e.g. Ocusert®, a trademark of Alza Corp.) This last solution has not been very successful because of a low degree of patient compliance, due to irritation, difficulty in insertion, and over-extended retention.
Viscosified solutions or gels have been accepted to a greater degree by patients, among other things, because of the ease of administration, lack of irritation of the eye as a result of administration thereto, and lower cost compared to other treatment methods. However, existing formulations of viscosified solutions only increase residence time of a drug in the eye to a limited extent, so the same solution must be applied to an eye multiple times to treat or prevent a given illness or infection of the eye. Many of the marketed ophthalmic formulations currently use the polymers hydroxypropyl methylcellulose, hydroxyethyl cellulose, and polyvinyl alcohol to increase the viscosity of the formulation. Other viscosity enhancers disclosed as being suitable for use in ophthalmic formulations include, but are not limited to propylene glycol alginate (U.S. Pat. No. 4,844,902; U.S. Pat. No. 5,776,445), tragacanth (U.S. Pat. No. 5,369,095).
A basic and important characteristic of the systems described immediately above is their viscosity. However, simply enhancing the viscosity of an ophthalmic formulation is not sufficient. Pseudo-plastic formulations that show a reduced viscosity upon shear are of great interest since such formulations support ocular movement and blinking leading to greater acceptability than simple viscous Newtonian formulations. Shear rates associated with normal blinking range from 0 at rest to 10,000 s−1 during blinking. Gel systems exhibiting critical yield behavior below these shear rates are also comfortable when dosed.
A degree of mucoadhesivity is also advantageous in such systems. The best bioadhesive polymers have been found to be polyanions such as polyacrylic acid.
A variation of viscosified solutions has been the use of in-situ gelling systems which have the advantage that the formulation is easy to instill due to its fluid nature, but the in-situ gelling ability allows for increased retention in the eye. Gelling occurs as a result of ion concentration change or temperature change. Examples of polymers incorporated into ophthalmic formulations to promote in situ gelling include, but are not limited to, xanthan gum (U.S. Pat. No. 6,174,524 B1), xanthan gum and locust bean gum (See U.S. Pat. Nos. 4,136,173; 4,136,177; and 4,136,178), gellan gum (U.S. Pat. No. 4,861,760), carageenans (EP 0 424 043 A1; U.S. Pat. No. 5,403,841), cellulose and derivatives thereof including Carbopol® (trademark of B.F. Goodrich) (U.S. Pat. No. 5,888,493 and U.S. Pat. No. 5,710,182), hydroxypropyl guar (WO 99/06023), pectin (EP 0 312 208; WO 98/47535), and a sulfated glucan sulfate such as β-1,3-glucan sulfate (U.S. Pat. No. 5,227,372; U.S. Pat. No. 5,135,920).
A limited number of combinations of gells have also been disclosed as being suitable for use in ophthalmic formulations. For example, U.S. Pat. No. 5,212,162 indicates that one could use “xanthan gum, locust bean gum, gellan gum, carrageenens, and combinations thereof.” (col. 2, lines 11–14). However, no examples of even a single formulation containing any such combination is provided therein. The only examples illustrated the manufacture and use of formulations containing only a single species of gum per solution. Therefore, it is unclear, from that patent, whether any such combinations would actually work.
WO 01/96461 discloses fluid gels of xanthan and non-gelling polysaccharides, such as konjac mannan, tara, locust bean, and guar gum for use in a variety of different cosmetic applications (e.g. in a bath gel, a shower gel, a shampoo, an antiperspirant, a face mask, etc.). However, that international application publication does not suggest that particular combination would be suitable for use in an ophthalmic formulation or method of application of an active agent to an eye.
A summary of the viscosified/bioadhesive and in-situ gelling systems can also be found in Le Bourlais et al, Progr. Retinal & Eye Res. 17: 33–58 (1998).
There remains a need for simple, low cost ophthalmic formulations that provide enhanced viscosity and/or gel forming capability in the eye than is possible with existing formulations. The present ophthalmic formulations and gum systems meet the needs discussed above, as becomes apparent from the description and illustration of the present invention, below.